Enantioselective enolate protonation in sulfamichael addition to r-substituted n-acryloyloxazolidin-2-ones with bifunctional organocatalyst

Article abstract of DOI:10.1021/ol202808n

Organocatalytic conjugate addition of thiols to R-substituted N-acryloyloxazolidin-2-ones followed by asymmetric protonation has been studied in the presence of cinchona alkaloid derived thioureas. Both of the enantiomers are accessible with the same level of enantioselectivity using pseudoenantiomeric quinine/quinidine derived catalysts. The addition/protonation products have been converted to useful biologically active molecules. 2011 American Chemical Society.

Full text of DOI:10.1021/ol202808n

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6520–6523
Enantioselective Enolate Protonation in
SulfaꢀMichael Addition to r-Substituted
N-Acryloyloxazolidin-2-ones with
Bifunctional Organocatalyst
Nirmal K. Rana† and Vinod K. Singh*,‡,†
Department of Chemistry, Indian Institute of Technology Kanpur, India, 208 016, and
Department of Chemical Sciences, Indian Institute of Science Education and Research
Bhopal, ITI (Gas Rahat) Building, Govindpura, India 460 023
vinodks@iitk.ac.in
Received October 19, 2011
ABSTRACT
Organocatalytic conjugate addition of thiols to R-substituted N-acryloyloxazolidin-2-ones followed by asymmetric protonation has been studied in the
presence of cinchona alkaloid derived thioureas. Both of the enantiomers are accessible with the same level of enantioselectivity using
pseudoenantiomeric quinine/quinidine derived catalysts. The addition/protonation products have been converted to useful biologically active molecules.
Enantioselective protonation of a prostereogenic enol-
(ate) derivative is a fundamental concept and has been
shown to be a powerful practical method for the prepara-
tion of enantiomerically enriched carbonyl compounds
which possess a tertiary asymmetric carbon at the
R-position.1 Tertiary carbon stereocenters are extremely
common structural motifs in valuable biologically active
natural products and pharmaceutical agents.2 The creation
of a stereogenic center by the formation of a CꢀH bond
using enantioselective transfer of a proton to an enolate
intermediate remains a worthwhile goal. A number of
chemical methods exist for enantioselective protonation
by exploring various means of enantiocontrol in different
mechanisms. The majority of work in this area has been
directed toward the use of isolated enolate precursors, such
as silyl enol ethers,3 and a stoichiometric amount of chiral
proton sources.4 Enol ethers (or enolate) derived from
R-substituted cyclic ketones have been widely investigated.
However, the employment of preformed acyclic enolate
derivatives for this reaction are sparse.5 An attractive
alternative is the generation of a transient enolate by the
conjugate addition of a nucleophile to an R-substituted
(3) For recent examples, see: (a) Poisson, T.; Dalla, V.; Marsais, F.;
Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46,
7090. (b) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,
9246. (c) Poisson, T.; Gembus, V.; Dalla, V.; Oudeyer, S.; Levacher, V.
J. Org. Chem. 2010, 75, 7704. (d) Cheon, C. H.; Imahori, T.; Yamamoto,
H. Chem. Commun. 2010, 46, 6980. (e) Uraguchi, D.; Kinoshita, N.; Ooi,
T. J. Am. Chem. Soc. 2010, 132, 12240.
(4) For selected examples, see: (a) Duhamel, L.; Plaquevent, J.-C.
J. Am. Chem. Soc. 1978, 100, 7415. (b) Yanagisawa, A.; Watanabe, T.;
Kikuchi, T.; Yamamoto, H. J. Org. Chem. 2000, 65, 2979. (c) Ishihara,
K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc.
1996, 118, 12854.
† Indian Institute of Technology Kanpur.
‡ Indian Institute of Science Education and Research Bhopal.
(1) (a) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nat. Chem. 2009, 1,
359. (b) Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron:
Asymmetry 2004, 15, 3653.
(2) (a) ApSimon, J., Ed. The Total Synthesis of Natural Products;
John Wiley & Sons: Ottawa, 1992; Vol. 9. (b) Jamali, F.; Mehvar, R.;
Russell, A. S.;Sattari, S.;Yakimets, W. W.;Koo, J.J. Pharm. Sci. 1992, 81,
221. (c) Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowoski,
A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203.
(5) For selected examples, see: (a) Vedejs, E.; Kruger, A. W.; Lee, N.;
Sakata, S. T.; Stec, M.; Suna, E. J. Am. Chem. Soc. 2000, 122, 4602.
(b) Wang, W.; Xu, M.-H.; Lei, X.-S.; Lin, G.-Q. Org. Lett. 2000, 2, 3773.
(c) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406.
r
10.1021/ol202808n
Published on Web 11/18/2011
2011 American Chemical Society

R,β-unsaturated carbonyl compound followed by an
in situ enantioselective protonation of the resulting tran-
sient enolate.6 In particular, the Michael addition of thiols
to R-substituted acrylates followed by enantioselective
protonation has been a challenging target.7 Sulfur-
containing chiral frameworks are useful building blocks
in many naturally occurring compounds and therapeuti-
cally active molecules.8 Implication of a sulfur functional
group in synthetic organic chemistry is extremely high be-
cause it can be selectively removed or subjected to late stage
transformations.7c Cinchona derivatives have recently
emerged as efficient organocatalysts for different reactions.9
Quite efficient catalytic asymmetric sulfa-Michael addition
reactions using a cinchona alkaloid derived catalyst have
been achieved.10 In contrast, the organocatalytic asymmetric
protonation via sulfa-Michael addition has not yet been
achieved to a synthetically useful level.11 The success in
enantioselective protonation of a transient acyclic enolate
solely depends on rotamer control of the enolate configura-
tion.12 Thus, the appropriate choice of a prochiral template
and chiral catalyst is important. Here, we report an effective
catalytic sulfa-Michael addition to R-substituted N-acryloy-
loxazolidin-2-ones followed by enantioselective protonation
by using cinchona alkaloid derived thioureas.
protonation to R-methyl acrylate acceptors. After screen-
ing different prochiral templates for the reaction using
1a as a catalyst, 3-methacryloyloxazolidin-2-one 2b was
found to be the best in terms of selectivity. Therefore,
further optimization was carried out using 2b as a model
template. Several reaction parameters were examined to
improve the selectivity, and it was found that 2b gave a
promising enantioselectivity (85% ee) and excellent yield
(99%) with catalyst 1a (1 mol %) in toluene at rt.13
Our initial studies began to identify the combination of
prochiral template and chiral catalyst that could provide
high reactivity and selectivity in sulfa-Michael addition/
Figure 1. Cinchona alkaloid derived thiourea catalysts.
After initial optimization of the reaction conditions with
1a, various cinchona alkaloid derived thiourea catalysts
(Figure 1) were screened in the above reaction, and the
results are summarized in Table 1. The enantioselectivities
varied greatly depending on the organocatalysts used.
Moderate enantioselectivity with catalysts 1c emphasizes
the importance of the correct relative orientation of
thiourea and quinuclidine functional groups in the cata-
lyst’s chiral scaffold (Table 1, entry 3). Sulfa-Michael
addition/protonation product 3b, enriched in the opposite
enantiomer, was obtained with catalyst 1dꢀe (Table 1,
entries 4 and 5). Thus, access to both enantiomers was
found to be possible with the same level of enantioselec-
tivity. The thiourea catalyst 1a was found to be superior
over the corresponding urea 1f. The moderate enantio-
meric excess with catalysts 1gꢀh clearly indicates that the
CF3 substituent on the aromatic ring is crucial for high ee.
When 60-cinchona thiourea 1i was used for the reaction, a
low ee was observed. The result indicates that the appro-
priate distance between acidic and basic groups is impor-
tant for a high ee. Catalysts 1jꢀk having an additional
chiral center were also tested in the above reaction, but
poor enantioselectivities were observed. Mixing the race-
mic 3b in optimum reaction conditions did not show any ee
even after 24 h, suggesting that the kinetic control is
probably responsible for the observed results.14 Next, we
tried to recover the catalyst. Yet, it was unsucessful for
such a small scale reaction.
(6) (a) Wilcke, F.-W.; Hanemann, K. J. Prakt. Chem. 1977, 319, 219.
(b) Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.; Sacramento, J.
J. Chem. Soc., Perkin Trans. 1 2001, 3167. (c) Belokon, Y. N.;
Harutyunyan, S.; Vorontsov, E. V.; Peregudov, A. S.; Chrustalev,
V. N.; Kochetkov, K. A.; Pripadchev, D.; Sagyan, A. S.; Beck, A. K.;
Seebach, D. ARKIVOC 2004, 132. (d) Hamashima, Y.; Somei, H.;
Shimura, Y.; Tamura, T.; Sodeoka, M. Org. Lett. 2004, 6, 1861.
(e) Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004,
43, 719. (f) Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571.
(g) Frost, C. G.; Penrose, S. D.; Lambshead, K.; Raithby, P. R.; Warren,
J. E.; Gleave, R. Org. Lett. 2007, 9, 2119. (h) Navarre, L.; Martinez, R;
Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159. (i) Morita,
M.; Drouin, L.; Motoki, R.; Kimura, Y.; Fujimori, I.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3858. (j) Poisson, T.;
Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2010, 132, 7890. (k)
Duan, S.-W.; An, J.; Chen, J.-R.; Xiao, W.-J. Org. Lett. 2011, 13, 2290.
(7) (a) Tsai, W.-J.; Lin, Y.-T.; Uang, B.-J. Tetrahedron: Asymmetry
1994, 5, 1195. (b) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am.
Chem. Soc. 1998, 120, 4043. (c) Nishimura, K.; Ono, M.; Nagaoka, Y.;
Tomioka, K. Angew. Chem., Int. Ed. 2001, 40, 440. (d) Henze, R.;
Duhamel, L.; Lasne, M.-C. Tetrahedron: Asymmetry 1997, 8, 3363.
(e) Monteil, T.; Danvy, D.; Sihel, M.; Leroux, R.; Plaquevent, J.-C.
Mini-Rev. Med. Chem. 2002, 2, 209.
(8) (a) Abe, K.; Inoue, H.; Ikezaki, M.; Takeo, S. Chem. Pharm. Bull.
1971, 19, 595. (b) Ondetti, M. A.; Rubin, B.; Cushman, D. W. Science
1977, 196, 441.
(9) Song, C. E., Ed. Cinchona Alkaloids in Synthesis and Catalysis;
WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2009.
(10) (a) Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem.
2010, 75, 2089. (b) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L.
J. Am. Chem. Soc. 2009, 131, 418. (c) Dai, L.; Wang, S.-X.; Chen, F.-E.
Adv. Synth. Catal. 2010, 352, 2137. (d) Ricci, P.; Carlone, A.; Bartoli, G.;
Bosco, M.; Sambri, L.; Melchiorre, P. Adv. Synth. Catal. 2008, 350, 49.
(e) McDaid, P.; Chen, Y.; Deng, L. Angew. Chem., Int. Ed. 2002, 41, 338.
(f) Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang, W. J. Am. Chem.
Soc. 2007, 129, 1036.
(11) (a) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y.
J. Chem. Soc., Chem. Commun. 1991, 485. (b) Li, B.-J.; Jiang, L.; Liu,
M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. (c) Leow, D.;
Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed.
2008, 47, 5641.
(13) For details, see Supporting Information.
(14) A control experiment was performed according to a reviewer’s
comment. We thank the reviewer for his valuable suggestion.
(12) Sibi, M. P.; Coulomb, J.; Stanley, L. M. Angew. Chem., Int. Ed.
2008, 47, 9913.
Org. Lett., Vol. 13, No. 24, 2011
6521

Having identified the optimized conditions for this re-
action, a variety of thiols were then tested by using 2b as a
Michael acceptor (Table 2). Next, we investigated the scal-
ability of the reaction. A 10-fold increase in the scale re-
sultedin comparable yieldsand enantioselectivity(Table 2,
entry 2). Then we conducted the reaction of 2b with a
variety of thiols. Good to high enantioselectivities were
obtained in almost all the cases. It is noteworthy that the
electronic nature and the steric hindrances of the substi-
tuents on the aromatic ring of thiols have little effect on the
enantioselectivity. Less reactive aliphatic thiols were also
employed for this reaction, and high ee’s were achieved in
all the cases (Table 2, entries 16ꢀ19). Yet, a longer reaction
time was required for the completion of the reaction.
A heteroaromatic thiol, namely 2-pyrimidine thiol, was
reacted smoothly with 2b and furnished the product 3y
with 82% ee (Table 2, entry 20).
To extend the scope of the reaction, Michael addition/
protonation of thiophenol with structurally different
R-substituted N-acryloyl oxazolidinones (4aꢀn) were stu-
died. Useful enantioselectivities were achieved with a wide
variety of substituents (Table 3). The electronic nature of
the substituent on the aromatic ring of Michael acceptors
has little effect on the product ee (Table 3, entries 7ꢀ9).
Table 1. Screening of Different Chiral Catalystsa
entry
catalyst
yield (%)
ee (%)b
1c
2
1a
1b
1c
1d
1e
1f
99
97
95
99
97
93
90
97
98
96
96
85
83
70
84
83
63
50
42
30
20
36
3
4d
5d
6
7
1g
1h
1i
8
9
10
11
1j
1k
a Reactions were carried out on 0.2 mmol of 2b and 0.24 mmol of
thiophenol in 1 mL of toluene with 0.002 mmol of catalyst 1 at rt, unless
noted otherwise. b Determined by HPLC using a chiral column. c Abso-
lute stereochemistry was determined to be (R). d Opposite enantiomer as
major was obtained.
Table 2. Conjugate Addition of Different Thiols to Prochiral
Template 2b Followed by Enantioselective Protonationa
Table 3. Conjugate Addition of Thiol to Different R-Substituted
N-Acryloyl Oxazolidinones Followed by Enantioselective Pro-
tonationa
time
(h)
yield
(%)
eeb
(%)
R1 4
product
yield (%)
eeb (%)
entry
R
product
entry
1
Ph
Ph
12
12
12
12
12
12
12
9
3b
3b
3h
3i
99
97
95
94
96
94
98
99
99
99
99
98
97
94
98
94
92
85
86
98
85
81
78
76
80
81
86
80
73
76
70
84
83
85
65
82
79
89
90
82
1
Ph 4a
Ph 4a
5a
5a0
99
98
99
99
97
97
98
98
82
98
96
98
98
98
98
98
95
96
96
88
87
73
82
77
80
96
94
95
80
82
84
83
89
92
83
93
81
83
2c
3
2c
3
4-MeO-C6H4
2-MeO-C6H4
4-Me-C6H4
2-Me-C6H4
4-tBu-C6H4
4-F-C6H4
4-Cl-C6H4 4b
5b
4
4
4-F-C6H4 4c
5c
5
3j
5
4-MeO-C6H4 4d
3-MeO-C6H4 4e
2-MeO-C6H4 4f
2-MeO-C6H4 4f
2-MeO-C6H4 4f
4-Me-C6H4 4g
5d
6
3k
3l
6
5e
7
7
5f
5f0
5f00
8d
9e
10
11
12
13
14
15f
16
17
18
19f
8
3m
3n
3o
3p
3q
3r
3s
9
2-F-C6H4
10
9
10
11
12
13
14
15
16d
17d
18d
19d
20
4-Cl-C6H4
5g
2-Cl-C6H4
10
12
14
14
8
3-Me-C6H4 4h
4-tBu-C6H4 4i
4-nBu-C6H4 4j
4-iBu-C6H4 4k
4-iBu-C6H4 4k
2-naphthyl 4l
5h
4-Br-C6H4
2-Naphthyl
2-Et-C6H4
2-H2N-C6H4
PhCH2
4-tBu-C6H4CH2
4-MeO-C6H4CH2
furfuryl
5i
5j
5k-(R)
5k-(S)
5l
3t
72
72
72
72
18
3u
3v
3w
3x
3y
1-naphthyl 4m
2-(6-MeO-naphthyl) 4n
2-(6-MeO-naphthyl) 4n
5m
5n-(R)
5n-(S)
2-pyrimidine
a Reactions were carried out on a 0.2 mmol scale with 0.24 mmol of
thiol in 1 mL of toluene at rt, unless noted otherwise. b Determined by
HPLC using chiral column. c 2-Aminothiophenol was used. d 2-
Naphthylthiol was used. e 4-Methoxytoluenethiol (3 equiv) was used,
and reaction was continued for 72 h. f Catalyst 1d was used.
a Reactions were carried out on a 0.2 mmol scale with 0.24 mmol of
thiol in 1 mL of toluene at rt, unless noted otherwise. b Determined by
HPLC using chiral column. c Reaction was carried out on a 2 mmol
scale. d 3 equiv of thiol were used.
6522
Org. Lett., Vol. 13, No. 24, 2011

However, the position of the substituents on the aromatic
ring has a dramatic effect on enantioselectivity. Interest-
ingly, 2-(o-methoxyphenyl) acryloyloxazolidin-2-one 4f
furnished the corresponding products in excellent enan-
tioselectivities (up to 96% ee) (Table 3, entries 7ꢀ9). For
two typical cases, both enantiomers were achieved with the
same level of enantioselectivity by using two pseudoenan-
tiomeric catalysts 1a and 1d (Table 3, entries 15 and 19).
Then, we challenged the method by testing its efficiency
with an R,β-substituted R,β-unsaturated carbonyl com-
pound. Reaction of thiophenol with 6, sulfa-Michael
addition, and ptotonation led to the desired product 6a
with moderate dr and excellent ee of the major diastereo-
mer. The product was later transformed to the corre-
sponding methyl ester 7 without any detectable
epimerization (Scheme 1).13
anti-inflammatory drugs (NSAIDs) in 99% enantiopure
form in good yields (Scheme 2).
The proposed transition state models to explain the
stereochemical outcome of the reaction are shown in
Figure 2. We believe that 3-methacryloyloxazolidin-2-
one is activated by the thiourea moiety through
double hydrogen bonding, while the aromatic thiol is
activated by the tertiary nitrogen of the quinuclidine.
Michael addition of thiolate to 2b generates a transient
ion pair. Subsequent delivery of the proton from the
quinuclidine nitrogen to the Si face of the generated
prochiral enolate leads to the formation of the major
stereoisomer.11a,12
Scheme 1. Catalytic Asymmetric Sulfa-Michael Addition/
Protonation
Figure 2. Proposed transition state models.
Finally, the synthetic potential of the protonated pro-
ducts was demonstrated. The adduct 3b was converted to 8
in high yield without compromising the optical purity. The
transformation also led us to determine the absolute con-
figuration of 3b (R)13 (Scheme 2). Addition/protonation
products 3t and 5a0 were successfully converted to the cor-
responding cyclic amides 9 and 10, the core structure
of diltiazem,8a without affecting the ee’s. Desulfurization
with Raney Nickel W-2 followed by basic hydrolysis
of 5k-(S) and 5n-(S) gave the corresponding chiral acids
without racemization. Recrystallization of these chiral
acids from benzene enabled us to obtain analytically
pure (S)-Ibuprofen2b and (S)-Naproxen,2c nonsteroidal
In conclusion, we have developed an effective catalytic
sulfa-Michael addition to R-substituted N-acryloyloxazo-
lidin-2-ones followed by enantioselective protonation by
using cinchona alkaloid derived thiourea catalysts. This
protocol offers several advantages suchas operational sim-
plicity, mild reaction conditions, low catalyst loading (1
mol %), good to excellent enantioselectivities (up to 96%
ee), and quantitative yields. Both enantiomers of addition/
protonation products could be achieved with the same
level of enantioselectivity. The synthetic utility of the
present catalytic asymmetric protonation reaction was
established by transforming the products to useful mole-
cules, such as (S)-Ibuprofen and (S)-Naproxen, used
clinically as NSAIDs. Further studies focusing on the full
scope of the catalytic system are currently underway in our
laboratory.
Scheme 2. Applications of the Sulfa-Michael Addition/Proto-
nation Products
Acknowledgment. V.K.S. thanks the Department of
Science and Technology, India for a research grant
through a J. C. Bose fellowship. N.K.R. thanks the
Council of Scientific and Industrial Research, New
Delhi for a research fellowship. N.K.R. also thanks
Dr. Pradeep K. Singh (Department of Chemistry, Indian
Institute of Technology Kanpur, India) and Dr. Alakesh
Bisai (Department of Chemical Sciences, Indian
Institute of Science Education and Research Bhopal) for
their help.
Supporting Information Available. Experimental pro-
cedures and spectral data for all products. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org
Org. Lett., Vol. 13, No. 24, 2011
6523